History of Changes for Study: NCT03734588

Dose-finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors

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Study Record Versions

Version	Submitted Date	Changes
1	November 7, 2018	None (earliest Version on record)
2	November 12, 2018	Study Description, Oversight and Study Status
3	December 13, 2018	Recruitment Status, Study Status and Contacts/Locations
4	March 11, 2019	Contacts/Locations, Study Status and IPDSharing
5	December 3, 2019	Study Status and Contacts/Locations
6	May 14, 2020	Recruitment Status, Study Status and Contacts/Locations
7	October 30, 2020	Study Status
8	January 15, 2021	Study Status
9	February 3, 2022	Recruitment Status, Contacts/Locations and Study Status
10	July 15, 2022	Contacts/Locations and Study Status
11	October 28, 2022	Contacts/Locations and Study Status
12	January 18, 2023	Study Status
13	February 21, 2023	Recruitment Status, Study Status, Contacts/Locations and Study Design
14	January 18, 2024	Quality Control Review has not concluded Returned: February 12, 2024 Recruitment Status, Study Status, Outcome Measures, Document Section, Eligibility and Study Description
15	February 22, 2024	Study Status, Outcome Measures and Participant Flow

Comparison Format:

Merged
Side-by-Side

Study Identification


Unique Protocol ID:	SPK-8016-101
Brief Title:	Dose-finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors
Official Title:	Dose-finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors
Secondary IDs:

Study Status


Record Verification:	February 2024
Overall Status:	Completed
Study Start:	January 30, 2019
Primary Completion:	October 14, 2020 [Actual]
Study Completion:	January 19, 2023 [Actual]

First Submitted:	November 6, 2018
First Submitted that Met QC Criteria:	November 7, 2018
First Posted:	November 8, 2018 [Actual]

Results First Submitted:	January 18, 2024
Results First Submitted that Met QC Criteria:	February 22, 2024
Results First Posted:	February 23, 2024 [Actual]

Last Update Submitted that Met QC Criteria:	February 22, 2024
Last Update Posted:	February 23, 2024 [Actual]

Sponsor/Collaborators


Sponsor:	Spark Therapeutics, Inc.
Responsible Party:	Sponsor
Collaborators:

Oversight


U.S. FDA-regulated Drug:	Yes
U.S. FDA-regulated Device:	No
Data Monitoring:	Yes

Study Description


Brief Summary:	SPK-8016 is in development for the treatment of patients with inhibitors to FVIII. This Phase 1/2, open-label, non-randomized, dose-finding study to evaluate the safety, efficacy, and tolerability of SPK-8016 in adult males with severe hemophilia A and no measurable inhibitor against FVIII.
Detailed Description:

Conditions


Conditions:	Adeno-Associated Virus (AAV) Blood Coagulation Disorder Blood Coagulation Disorders, Inherited Coagulation Protein Disorders Factor VIII (FVIII) Factor VIII (FVIII) Deficiency Factor VIII (FVIII) Gene Factor VIII (FVIII) Protein Genetic Diseases, Inborn Genetic Diseases, X-Linked Gene Therapy Gene Transfer Hematologic Diseases Hemorrhagic Disorders Recombinant Vector Inhibitors
Keywords:

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 1/Phase 2
Interventional Study Model:	Single Group Assignment
Number of Arms:	1
Masking:	None (Open Label)
Allocation:	N/A
Enrollment:	4 [Actual]

Arms and Interventions

Arms	Assigned Interventions
Experimental: SPK-8016 All participants who meet the eligibility criteria will receive an outpatient single intravenous (i.v.) administration of SPK-8016.	Genetic: SPK-8016 adeno-associated viral vector

Outcome Measures

[See Results Section.]


Primary Outcome Measures:
1.	Number of Participants With Adverse Events (AEs) [ Time Frame: Up to week 52 ] An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
2.	Number of Participants With Hepatic Transaminase Elevation Requiring Immunosuppression. [ Time Frame: Up to week 52 ]
3.	Peak FVIII Activity Levels Assessed by Coagulation Clotting Assays [ Time Frame: Up to week 52 ]
4.	Steady-state FVIII Activity Levels Assessed by Coagulation Clotting Assays [ Time Frame: Up to week 52 ]
5.	Number of Bleeding Events (Spontaneous and Traumatic) Since 28 Day Post Vector Administration [ Time Frame: From 28 days post vector administration up to week 52 ]
6.	Annualized Infusion Rate [ Time Frame: From 28 days post vector administration up to week 52 ]
Secondary Outcome Measures:
1.	Time to Achieve Steady-state FVIII Activity Levels [ Time Frame: Up to week 52 ]
2.	Number of Participants With Vector-shedding of SPK-8016 in Bodily Fluids [ Time Frame: Up to week 52 ]
3.	Number of Participants With Immune Responses to AAV Capsid Protein and BDD-hFVIII Transgene [ Time Frame: Up to week 52 ]

Eligibility


Minimum Age:	18 Years
Maximum Age:
Sex:	Male
Gender Based:	Yes
	Genetically male
Accepts Healthy Volunteers:	No
Criteria:	Inclusion Criteria: Be male and ≥18 years of age; Have clinically severe hemophilia A, defined as: <1% (<1 IU/dL) endogenous FVIII activity levels as historically documented by a certified laboratory or screening data results; OR 1-2% (1-2 IU/dL) endogenous FVIII activity levels and > 10 bleeding events per year (in the last 52 weeks prior to screening); OR 1-2% (1-2 IU/dL) endogenous FVIII activity levels and on prophylaxis; Have had >150 exposure days (EDs) to any recombinant and/or plasma-derived FVIII concentrates or cryoprecipitates Have no prior history of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration Have no measurable inhibitor against FVIII as assessed by central laboratory, have no confirmed history of clinically significant FVIII inhibitor, and no clinical signs or symptoms of decreased response to FVIII administration (Note: family history of inhibitors will not exclude study participation) Agree to use reliable barrier contraception after the administration of SPK-8016 until notified by the Investigator. Exclusion Criteria: Have active hepatitis B or C Have significant underlying liver disease. Have serological evidence of HIV-1 or HIV-2 with CD4 counts ≤200/mm3. Participants who are HIV-positive and stable, with an adequate CD4 count (>200/mm3) and undetectable viral load, and are on an antiretroviral drug regimen are eligible to enroll Have detectable antibodies reactive with AAV-Spark capsid Have history of chronic infection or other chronic disease Have been dosed in a previous gene therapy research trial within the last 52 weeks or with an investigational drug within the last 12 weeks Any concurrent clinically significant major disease (such as liver abnormalities or type I diabetes) or other condition that, in the opinion of the Investigator and/or Sponsor, makes the subject unsuitable for participation in the study; Unable or unwilling to comply with the schedule of visits and study assessments described in the clinical protocol.

Contacts/Locations


Study Officials:	Tiffany Chang, MD Study Director Spark Therapeutics, Inc.
Locations:	United States, California
	Orthopaedic Institute for Children Los Angeles, California, United States, 90007
	United States, Illinois
	Illinois Bleeding and Clotting Disorders Institute Peoria, Illinois, United States, 61615
	United States, Michigan
	University of Michigan Ann Arbor, Michigan, United States, 48109
	United States, Mississippi
	Mississippi Center for Advanced Medicine Madison, Mississippi, United States, 39110
	United States, New York
	Weill Cornell Medicine New York, New York, United States, 10065
	United States, Oregon
	Oregon Health & Science University Portland, Oregon, United States, 97239
	United States, Pennsylvania
	Penn State Health Hershey, Pennsylvania, United States, 17033
	Children's Hospital of Philadelphia Philadelphia, Pennsylvania, United States, 19104
	Jefferson University Hospitals Philadelphia, Pennsylvania, United States, 19107
	Hemophilia Center of Western Pennsylvania Pittsburgh, Pennsylvania, United States, 15213
	United States, Virginia
	Virginia Commonwealth University School of Medicine Richmond, Virginia, United States, 23219

IPDSharing


Plan to Share IPD:	No

References


Citations:
Links:
Available IPD/Information:

Document Section


	Study Protocol Document Date: March 19, 2021 Uploaded: 01/18/2024 17:00 File Name: Prot_000.pdf
	Statistical Analysis Plan Document Date: March 19, 2021 Uploaded: 01/18/2024 17:01 File Name: SAP_001.pdf

Participant Flow

Recruitment Details

Pre-assignment Details

A dose-finding part of this trial was planned but no participants were enrolled into the higher dose arms. All participants received SPK-8016 5x10^11 vg/kg

Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vector genomes per kilogram body weight (vg/kg).

Period Title: Overall Study
Started	4
Completed	4
Not Completed	0

Baseline Characteristics


Arm/Group Title		SPK-8016
Arm/Group Description		Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Baseline Participants		4
Baseline Analysis Population Description
Age, Continuous Mean (Standard Deviation) Unit of measure: years	Number Analyzed	4 Participants
		36.3(19.29)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	4 Participants
	Female	0 0%
	Male	4 100%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	4 Participants
	Hispanic or Latino	0 0%
	Not Hispanic or Latino	4 100%
	Unknown or Not Reported	0 0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	4 Participants
	American Indian or Alaska Native	0 0%
	Asian	0 0%
	Native Hawaiian or Other Pacific Islander	0 0%
	Black or African American	0 0%
	White	4 100%
	More than one race	0 0%
	Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome:

Title

Number of Participants With Adverse Events (AEs)

Description

An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Time Frame

Up to week 52

Outcome Measure Data

Analysis Population Description

The FAS included all enrolled participants who received the infusion of SPK-8016.


Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Participants Analyzed	4
Measure Type: Count of Participants Unit of Measure: Participants	4 100%

2. Primary Outcome:

Title

Number of Participants With Hepatic Transaminase Elevation Requiring Immunosuppression.

Description

Time Frame

Up to week 52

Outcome Measure Data

Analysis Population Description

The FAS included all enrolled participants who received the infusion of SPK-8016.


Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Participants Analyzed	4
Measure Type: Count of Participants Unit of Measure: Participants	0 0%

3. Primary Outcome:

Title

Peak FVIII Activity Levels Assessed by Coagulation Clotting Assays

Description

Time Frame

Up to week 52

Outcome Measure Data

Analysis Population Description

The FAS included all enrolled participants who received the infusion of SPK-8016.


Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Participants Analyzed	4
Measure Type: Number Unit of Measure: percentage of normal activity	NA^[1]

[1]	NA Explanation: Data was not analyzed due to low number of participants enrolled. Data values are not reported due to privacy concerns related to low enrollment.

4. Primary Outcome:

Title

Steady-state FVIII Activity Levels Assessed by Coagulation Clotting Assays

Description

Time Frame

Up to week 52

Outcome Measure Data

Analysis Population Description

The FAS included all enrolled participants who received the infusion of SPK-8016.


Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Participants Analyzed	4
Mean (Standard Deviation) Unit of Measure: percentage of normal activity	NA(NA)^[1]

[1]	NA Explanation: Insufficient number of participants with events

5. Primary Outcome:

Title

Number of Bleeding Events (Spontaneous and Traumatic) Since 28 Day Post Vector Administration

Description

Time Frame

From 28 days post vector administration up to week 52

Outcome Measure Data

Analysis Population Description

The FAS included all enrolled participants who received the infusion of SPK-8016.


Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Participants Analyzed	4
Measure Type: Number Unit of Measure: Number of bleeding events
Traumatic	6 150%
Spontaneous	1 25%

6. Primary Outcome:

Title

Annualized Infusion Rate

Description

Time Frame

From 28 days post vector administration up to week 52

Outcome Measure Data

Analysis Population Description

The FAS included all enrolled participants who received the infusion of SPK-8016.


Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Participants Analyzed	4
Measure Type: Number Unit of Measure: Annualized Infusion Rate	NA^[1]

[1]	NA Explanation: Data was not analyzed due to low number of participants enrolled. Data values are not reported due to privacy concerns related to low enrollment.

7. Secondary Outcome:

Title

Time to Achieve Steady-state FVIII Activity Levels

Description

Time Frame

Up to week 52

Outcome Measure Data

Analysis Population Description

The FAS included all enrolled participants who received the infusion of SPK-8016.


Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Participants Analyzed	4
Mean (Standard Deviation) Unit of Measure: hours	NA(NA)^[1]

[1]	NA Explanation: Insufficient number of participants with events

8. Secondary Outcome:

Title

Number of Participants With Vector-shedding of SPK-8016 in Bodily Fluids

Description

Time Frame

Up to week 52

Outcome Measure Data

Analysis Population Description

Results were uninterpretable due to a technical error.


Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Participants Analyzed	0
No data displayed because Outcome Measure has zero total participants analyzed.

9. Secondary Outcome:

Title

Number of Participants With Immune Responses to AAV Capsid Protein and BDD-hFVIII Transgene

Description

Time Frame

Up to week 52

Outcome Measure Data

Analysis Population Description

The FAS includes all enrolled participants who received the infusion of SPK-8016.


Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg.
Overall Number of Participants Analyzed	4
Measure Type: Count of Participants Unit of Measure: Participants	3 75%

Adverse Events


Time Frame	Up to week 52
Adverse Event Reporting Description	[Not specified]

Arm/Group Title	SPK-8016
Arm/Group Description	Participants received a single intravenous infusion of SPK-8016 at 5x10^11 vg/kg
All-Cause Mortality
	SPK-8016
	Affected / At Risk (%)
Total	0 / 4 (0%)
Serious Adverse Events
	SPK-8016
	Affected / At Risk (%)
Total	2 / 4 (50%)
Gastrointestinal disorders
Food Poisoning ^{† A}	1 / 4 (25%)
Haematemesis ^{† A}	1 / 4 (25%)
Musculoskeletal and connective tissue disorders
Back Pain ^{† A}	1 / 4 (25%)
†Indicates events were collected by systematic assessment. ATerm from vocabulary, MedDRA 24.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	SPK-8016
	Affected / At Risk (%)
Total	4 / 4 (100%)
Endocrine disorders
Cushingoid ^{† A}	1 / 4 (25%)
Eye disorders
Vision Blurred ^{† A}	1 / 4 (25%)
Gastrointestinal disorders
Abdominal Pain Upper ^{† A}	1 / 4 (25%)
Diarrhoea ^{† A}	1 / 4 (25%)
Dyspepsia ^{† A}	1 / 4 (25%)
Food Poisoning ^{† A}	1 / 4 (25%)
Nausea ^{† A}	1 / 4 (25%)
Tooth Loss ^{† A}	1 / 4 (25%)
Vomiting ^{† A}	1 / 4 (25%)
General disorders
Fatigue ^{† A}	1 / 4 (25%)
Feeling Hot ^{† A}	1 / 4 (25%)
Oedema Peripheral ^{† A}	1 / 4 (25%)
Swelling Face ^{† A}	1 / 4 (25%)
Hepatobiliary disorders
Drug-Induced Liver Injury ^{† A}	1 / 4 (25%)
Infections and infestations
Candida Infection ^{† A}	1 / 4 (25%)
Gastroenteritis Viral ^{† A}	1 / 4 (25%)
Nasopharyngitis ^{† A}	1 / 4 (25%)
Oral Herpes ^{† A}	1 / 4 (25%)
Pharyngitis Streptococcal ^{† A}	1 / 4 (25%)
Skin Infection ^{† A}	1 / 4 (25%)
Tooth Abscess ^{† A}	1 / 4 (25%)
Injury, poisoning and procedural complications
Contusion ^{† A}	1 / 4 (25%)
Limb Crushing Injury ^{† A}	1 / 4 (25%)
Scratch ^{† A}	1 / 4 (25%)
Skin Abrasion ^{† A}	1 / 4 (25%)
Skin Laceration ^{† A}	1 / 4 (25%)
Thermal Burn ^{† A}	1 / 4 (25%)
Tooth Fracture ^{† A}	1 / 4 (25%)
Investigations
Blood Glucose Increased ^{† A}	1 / 4 (25%)
Weight Increased ^{† A}	2 / 4 (50%)
Metabolism and nutrition disorders
Hyperglycaemia ^{† A}	1 / 4 (25%)
Musculoskeletal and connective tissue disorders
Arthralgia ^{† A}	2 / 4 (50%)
Joint Noise ^{† A}	1 / 4 (25%)
Joint Swelling ^{† A}	1 / 4 (25%)
Muscular Weakness ^{† A}	1 / 4 (25%)
Nervous system disorders
Dizziness ^{† A}	1 / 4 (25%)
Headache ^{† A}	2 / 4 (50%)
Hypoaesthesia ^{† A}	1 / 4 (25%)
Lethargy ^{† A}	2 / 4 (50%)
Psychiatric disorders
Anxiety ^{† A}	1 / 4 (25%)
Libido Decreased ^{† A}	1 / 4 (25%)
Renal and urinary disorders
Pollakiuria ^{† A}	1 / 4 (25%)
Respiratory, thoracic and mediastinal disorders
Cough ^{† A}	1 / 4 (25%)
Oropharyngeal Pain ^{† A}	2 / 4 (50%)
Pharyngeal Erythema ^{† A}	1 / 4 (25%)
Wheezing ^{† A}	1 / 4 (25%)
Skin and subcutaneous tissue disorders
Acne ^{† A}	1 / 4 (25%)
Pruritus ^{† A}	1 / 4 (25%)
Rash ^{† A}	1 / 4 (25%)
Skin Irritation ^{† A}	1 / 4 (25%)
†Indicates events were collected by systematic assessment. ATerm from vocabulary, MedDRA 24.0

Limitations and Caveats


[Not specified]

More Information


Certain Agreements:
Principal Investigators are NOT employed by the organization sponsoring the study. There IS an agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact:
Name/Official Title:	Tiffany Chang, MD, MAS Clinical Development Lead, Hematology
Organization:	Spark Therapeutics
Phone:	Please Email
Email:	Tiffany.chang@sparktx.com